Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition.

Diacylglycerol lipases (DAGLα and DAGLß) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLα is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network.

Piperidine and octahydropyrano[3,4-c] pyridine scaffolds for drug-like molecular libraries of the European Lead Factory.

We report short and efficient scalable syntheses of enantiomerically pure (3R,4S)-3-(hydroxymethyl4-(hydroxyethyl))-piperidine and 1-hydroxymethyl-octahydro-1H-pyrano[3,4-c]pyridine scaffolds. The alkaloid core was readily synthesized from naturally occurring quinine and can serve as a valued starting point for drug-discovery. Cleavage of a terminal 1,2-diol and acid catalysed epoxide opening cyclization are the key steps involved. A number of members of a projected small-molecular library is synthesized for each scaffold.

Synthetic and Organocatalytic Studies of Quinidine Analogues with Ring-Size Modifications in the Quinuclidine Moiety.

Six highly enantiopure analogues of [2.2.2] were synthesized with five- or seven-membered rings in the (original) quinuclidine skeleton. Five of these compounds were prepared through epoxide opening by a secondary cyclic amine, providing the nor- and homoquinuclidine moieties through five- and six-membered ring formation. This method failed in the case of seven-membered ring formation, so for that particular ring size a different synthetic route starting from 3-quinuclidone was applied. The six novel analogues were examined as organocatalysts in four asymmetric conjugate addition reactions and the results compared with those of known cinchona alkaloid catalysts. This study shows that modification of the quinuclidine ring can have a substantial influence on catalyst activity and enantioselectivity. To acquire more insight into the characteristics of the new catalysts, the pKaH values were determined by means of fluorescence spectroscopy. Furthermore, relative reaction rates of conjugate thiol additions reactions catalyzed by these quinidine analogues were measured through polarimetry.

Cinchona Alkaloid Catalyzed Sulfa-Michael Addition Reactions Leading to Enantiopure ß-Functionalized Cysteines.

Sulfa-Michael additions to α,ß-unsaturated N-acylated oxazolidin-2-ones and related α,ß-unsaturated α-amino acid derivatives have been enantioselectively catalyzed by Cinchona alkaloids functionalized with a hydrogen bond donating group at the C6' position. The series of Cinchona alkaloids includes known C6' (thio)urea and sulfonamide derivatives and several novel species with a benzimidazole, squaramide or a benzamide group at the C6' position. The sulfonamides were especially suited as bifunctional organocatalysts as they gave the products in very good diastereoselectivity and high enantioselectivity. In particular, the C6' sulfonamides catalyzed the reaction with the α,ß-unsaturated α-amino acid derivatives to afford the products in a diastereomeric ratio as good as 93:7, with the major isomer being formed in an ee of up to 99%. The products of the organocatalytic sulfa-Michael addition to α,ß-unsaturated α-amino acid derivatives were subsequently converted in high yields to enantiopure ß-functionalized cysteines suitable for native chemical ligation.

Expedient pyrrolizidine synthesis by propargylsilane addition to N-acyliminium ions followed by gold-catalyzed alpha-allenyl amide cyclization.

A reaction sequence, involving the addition of (substituted) propargylsilanes to lactam-derived N-acyliminium ions followed by gold-catalyzed cyclization of the resulting alpha-allenyl amide, is applied in expedient syntheses of pyrrolizidine alkaloids heliotridine and ent-retronecine in five steps from (S)-malic acid.

Acid-labile Cys-protecting groups for the Fmoc/tBu strategy: filling the gap.

To address the existing gap in the current set of acid-labile Cys-protecting groups for the Fmoc/tBu strategy, diverse Fmoc-Cys(PG)-OH derivatives were prepared and incorporated into a model tripeptide to study their stability against TFA. S-Dpm proved to be compatible with the commonly used S-Trt group and was applied for the regioselecive construction of disulfide bonds.